Longstanding Concern that Antidepressants May be Associated with the
Induction of Suicidality Early in Treatment

One of the goals of the February 2, 2004 meeting of the
Psychopharmacological Drugs Advisory Committee (PDAC) and the Pediatric
Subcommittee of the Anti-Infective Drugs Advisory Committee (Peds AC) is to
give you an update on the current status of our efforts to better understand
the suicidality data we have received from various drug development programs
involving the use of antidepressant drug products in pediatric patients.

The occurrence of suicidality in the context of treating patients
with depression and other psychiatric illnesses has been a concern and a topic
of interest and debate for decades.In
fact,antidepressant
labeling has, for many decades, carried the following standard language under
Precautions, alerting clinicians to closely monitor patients during initial
drug therapy out of concern for the possible emergence of suicidality:

“Suicide:The possibility
of a suicide attempt is inherent in major depressive disorder and may persist
until significant remission occurs. Close supervision of high-risk patients
should accompany initial drug therapy. Prescriptions for Drug X should be
written for the smallest quantity of tablets consistent with good patient
management, in order to reduce the risk of overdose.”

Of course, this standard Precautions statement does not explicitly
warn of the possibility that antidepressant drugs may have a causal role in the
emergence of suicidality early in treatment.While it is likely impossible at this point to trace the history of the
addition of this language to antidepressant labeling, I believe that, whether
explicit or not, the statement allows for that interpretation.In fact, as early as medical school, many
physicians learn of this concern, and it has been part of medical lore for many
decades that antidepressants may have an early activating effect that perhaps
gives depressed patients the energy to follow through on suicidal impulses
before the mood improvement associated with antidepressant treatment takes
effect.Following is a statement from a
textbook of psychiatry published over 40 years ago that is referring to
observations in patients during initial treatment with tricyclic
antidepressants [Slater and Roth’s
Clinical Psychiatry, by Bailliere, Tindall and Cassell; London, 1960, p. 231]:

“With beginning convalescence (following
initiation of treatment with tricyclic antidepressants), the risk of suicide
once more becomes serious as retardation fades.”

In fact, this particular mechanism proposed to explain a possible
increase in suicidality early in antidepressant treatment is so well known that
it is referred to as the “roll back” phenomenon.However, it is but one of several mechanisms
that have been proposed to explain the clinical observation that some patients
being treated with antidepressants, particularly early in treatment, may have
an increase in suicidality.This topic
was discussed at the September, 1991 meeting of the PDAC on this same issue,
and Dr. Martin Teicher provided a comprehensive list of the various mechanisms
that have been proposed:

Roll
back phenomenon: view that antidepressants with prominent energizing
effects may actually increase suicidal behavior in severely depressed
patients who are suicidal but also have psychomotor retardation and are
thus inhibited from acting on their suicidal thoughts.

Paradoxical
worsening of depression: view that, in rare patients, the depressed mood
may actually worsen as a result of antidepressant treatment.

Akathisia:
view that some antidepressants are associated with akathisia, and the
belief that akathisia may lead to suicidal behavior in certain depressed
patients.

Induction
of anxiety and panic attacks: view that certain antidepressants may induce
anxiety and panic attacks, and that these may lead to suicidal behavior in
certain depressed patients.

Stage
shifts: view that antidepressants may lead to switch from depression into
mixed states in bipolar depressed patients, and this may lead to
suicidality.

Insomnia:
view that insomnia associated with certain antidepressants may lead to
suicidal behavior in certain depressed patients.

While all of these have some plausibility as mechanisms for
explaining the clinical observation of worsening depression or suicidality in
depressed patients being treated with antidepressants, proposing a mechanism is
quite a different matter from demonstrating empirically that there is a causal
association between antidepressant use and induction of suicidality.Of course, this is the key question we hope
to be able to address with the suicidality data coming from the studies done
with various antidepressant drugs in pediatric patients, i.e., is there a
causal link between antidepressant drug use and suicidality in pediatric
patients with major depressive disorder or other psychiatric disorders.This is a critically important question to
answer, but it is equally important to answer it in a careful, thoughtful
manner.Erring in either direction would
have adverse consequences.Missing a
signal of increased risk of suicidality would result in greater comfort than is
warranted in the safety of these drugs in treating pediatric depression.On the other hand, a premature decision on
the strength of the signal could result in the overly conservative use of these
drugs, or their lack of availability entirely for the pediatric
population.Prematurely
reducing therapeutic options for this serious disease with well established
morbidity and mortality, quite apart from any role that antidepressant drugs
may have, does not seem like a good approach.In any case, the question is obviously timely
and important to fully address in order to understand how best to use these
drugs in the treatment of pediatric MDD.

If this view that initial antidepressant treatment may be associated
with an actual increase in risk of suicidality is in fact empirically
established, this would, in a sense, confirm a view that is already widely
prevalent in clinical lore, whatever the proposed mechanism.Despite this fairly widely held view,
however, the use of antidepressants has obviously increased over the years
rather than declined.This fact suggests
that, as a group, clinicians may place more weight on their beliefs in the
longer-term benefits of antidepressants than their concerns about possible
early risks of actually increased suicidal behavior.In fact, the dual findings of an early
increase in the risk of suicidality but also a longer-term benefit for this
same risk with antidepressant treatment would, if both true, not necessarily be
inconsistent.It is quite possible for a
drug to have opposite effects over time, even within the same domain.

Debate in Recent Years on the Question of Antidepressant-Induced
Suicidality in Adults

The debate on this question with regard to adult depression
intensified in 1990, at which time Martin Teicher, a psychiatrist from HarvardMedicalSchool, along with several colleagues, published a
paper describing a series of 6 adult patients with depression who, in their
view, became suicidal as a result of being treated with Prozac (fluoxetine) (Teicher, et al, 1990).This paper and the ensuing discussion led
Lilly, the manufacturer of Prozac, to conduct new analyses of their controlled
trials data for Prozac to explore for the emergence of suicidality.This renewed interest in the possible
induction of suicidality in association with the use of antidepressant
treatment also led FDA to fully re-evaluate its spontaneous reports database to
try to detect whether or not a signal of increased risk couldbe observed.Ultimately, this issue was brought to a PDAC
meeting in September, 1991.This one-day
meeting consisted of several hours of statements made by family members and
others in the open public session, and presentations by representatives from
FDA, Lilly, and NIMH.Statements in the
open session were made mostly by family members of suicide victims whose deaths
the families attributed to their taking Prozac.FDA gave an update on the very substantial number of spontaneous reports
of suicidality in association with Prozac use, but also showed how the pattern
of reporting was clearly linked to the publication of the Teicher, et al, paper
and other publicity about this concern.A representative from NIMH gave that agency’s perspective on this issue,
essentially making the case that depression is a serious disorder that itself
is associated with suicidality, and arguing that the data available to date did
not support the view that antidepressants further increase the risks of
suicidality in this population.Finally,
Lilly presented the results of its analysis of data pooled over its extensive
clinical trials, revealing no signal of increased suicidality in association
with the use of Prozac (Beasley, et al,
1991).At the end of a long day, a
majority of the committee concluded that there was no clear evidence of an
increased risk of suicidality in association with the use of Prozac, and they
did not recommend any changes to Prozac labeling with regard to this
issue.

Over the next several years, additional data were accumulated as applications
for newer antidepressants were submitted andreviewed, and these drugs came to
market.Several groups have, in recent
years, conducted pooled analyses for adult data on completed or attempted
suicides from these programs, in order to continue the search for a possible
signal of risk, either by virtue of being assigned to placebo, since the ethics
of conducting placebo controlled trials in depression were being challenged, or
due to assignment to drug treatment.Arif Khan, a psychiatrist from the NorthwestClinicalResearchCenter, Bellevue, Washington, published a paper in 2000 based on adult data
he obtained under FOI from FDA reviews.He concluded that the risk of completed suicide was the same, regardless
of treatment assignment (Khan, et al,
2000).Jitschak Storosum, a
physician from the Medicines Evaluation Board of the Netherlands, did an analysis of attempted suicides from
adult data available to his group, and he reached the same conclusion (Storosum, et al, 2001).FDA has done several analyses on completed
suicides for adult data sets provided to us in response to a request for
patient level data sets[1]for all
relevant studies involving 20 antidepressant drugs studied in 234 randomized
controlled trials with MDD.Based on our
initial analyses of these data, we have reached a similar conclusion, i.e.,
that there does not appear to be an increased risk of completed suicide
associated with assignment to either active drug or placebo in adults with MDD (Hammad, et al, 2003).

Source of Pediatric
Suicidality Data

Regarding pediatric suicidality, it is important first of all to
understand how it is that the various pediatric trials happen to have been
done.These trials were done largely in
response to a change in the Food, Drug and Cosmetic Act that authorized FDA to
grant additional marketing exclusivity (referred to as pediatric exclusivity)
to pharmaceutical manufacturers who were willing to conduct studies of their
drugs as requested by the FDA in pediatric populations.The first law permitting the pediatric
exclusivity incentive was the FDA Modernization Act (FDAMA, 1997), and this
authority to attach additional marketing exclusivity for such studies was
renewed in the Best Pharmaceuticals for Children Act (BCPA, 2001).In order to qualify for pediatric
exclusivity, sponsors had to conduct pediatric studies according to the terms
of a Written Request from FDA, and submit the results of those studies in a
pediatric supplement.We have reviewed 8
pediatric supplements over the past few years for pediatric drug development
programs involving antidepressant drugs that were conducted to gain additional
marketing exclusivity, and these supplements are the source of the pediatric
suicidality data that are at issue for this meeting.For
completeness, we have included in our review of pediatric suicidality two
studies for a ninth antidepressant drug for which the studies were not done for
exclusivity.Our review includes a total
of 24 studies for these 9 drugs, involving a total of over 4000 pediatric
patients.

The 9 drugs involved in our review are:

·Prozac
(fluoxetine)

·Zoloft
(sertraline)

·Paxil
(paroxetine)

·Luvox
(fluvoxamine)

·Celexa
(citalopram)

·Wellbutrin
(bupropion)

·Effexor
(venlafaxine)

·Serzone
(nefazodone)

·Remeron (mirtazapine)

Of the 24 studies for these 9 drugs, 15 were in MDD, 4 in OCD, 2 in
GAD, 1 in SAD, and 2 in ADHD.

Effectiveness Data for
Antidepressants in Pediatric MDD

While the focus of the discussion at the Feb 2nd PDAC
meeting will be on pediatric suicidality data, it is important to consider the
effectiveness data for these drugs as part of the overall context for this
discussion.Ultimately, this is a risk
benefit assessment, so it is important to know where we stand on the benefit
side of this issue.Of the 7 programs in
pediatric MDD (Prozac; Zoloft; Paxil; Celexa; Effexor; Serzone; Remeron), FDA’s
reviews of the effectiveness data resulted in only 1 approval for pediatric
MDD, i.e., for Prozac.The efficacy
results from the 15 studies in pediatric MDD are summarized in Appendix 1.

These are sobering findings and certainly raise a question about the
benefits of these drugs in pediatric depression,
however, the findings need to be considered in the context of several other
facts.

(1) In all but one case for the failed programs, there were only 2
studies in MDD; for the remaining failed program, there were 3 MDD
studies.Among the failed programs there
was one program where 1 of the studies was positive (citalopram), and 2 others
where the results, while negative by the usual standards, were at least
trending toward positive for 1 of the 2 studies (sertraline and
nefazodone).Of note, the published
literature gives a somewhat different perspective, suggesting more positivity
in 2 of these programs than was the conclusion at FDA.One paper describes one of the Paxil studies
as positive on most of the secondary endpoints, while acknowledging that it
failed on the primary endpoint (Keller,
et al, 2001).Another paper
describes the Zoloft program as positive, based on a pooling of 2 similarly
designed studies that, when looked at individually, failed (Wagner, et al, 2003).

In adult MDD programs for drugs that are approved for this
indication, overall, the failure rate for studies that appear in every respect
to be adequate trials is about 50%.Thus, if the failure rate were the same in pediatric MDD, it would not
be unexpected to have either 1 or both studies fail.In fact, since the studies can be considered
independent of one another, the probability of having one or both studies fail
in the 2-study programs is actually 0.75 [3(0.5 X 0.5)]; the probability of
both succeeding would be only 0.25 (0.5 X 0.5).Thus, under the best of circumstances, these very limited programs may
have been expected to mostly fail regarding the goal of obtaining 2 positive
studies.Nevertheless, the overall
success rate for positive studies of 20% (3/15) is clearly a concern.

(2) The history of pediatric MDD studies with the tricyclic
antidepressants (TCAs) is uniformly negative.This finding may have several possible explanations, including flaws in
design or conduct, or the possibility that TCAs simply do not work in pediatric
MDD.It is also possible, however, that
there is even greater heterogeneity among pediatric patients who meet criteria
for MDD than is true for adults.If
true, this would also work against obtaining positive studies in pediatric
MDD.

(3) The context in which these studies were conducted was not ideal,
in the sense that there was no need to obtain positive results in order to gain
exclusivity.The programs simply had to
be conducted according to the terms of the Written Requests, and the results
submitted to meet deadlines specified in those requests.This is not to suggest that sponsors of these
studies did not design and conduct them with good intent and according to high
standards, but rather, that the mindset was different than the usual mindset
for registration trials.Ordinarily, a
failure of a registration trial to show a drug effect is a complete loss.That was not the case here and this reality
could have influenced the conduct of the study in subtle ways that might have
worked against getting a positive result, e.g., in recruitment of
patients.

(4) Finally, there was not the kind of preliminary phase 2 dose
finding exploration for these studies that typically precedes definitive trials
in adult studies.We are routinely
asking for such exploration as part of the Written Requests we are now
issuing.

The point I am making is that there are several plausible reasons
for all but one of these programs failing, other than the possibility that
these drugs may have no benefits in pediatric MDD.It is understandable how some may have
reached the conclusion that these studies represent proof that these drugs,
with the exception of Prozac, have no benefits in pediatric MDD.We at FDA, however, do not view negative
studies as proof of no benefit.In our
view, absence of evidence for effectiveness in most of these programs does not
constitute evidence of absence of benefit for these drugs in pediatric
patients, for all the reasons noted above.Nevertheless, the failure of most of these programs to show a benefit in
MDD does heighten the concern about the possibility of certain risks that may
be associated with these drugs, in particular the concern about induction of
suicidality.In any case, the burden is
clearly upon those who believe these drugs do have benefits in pediatric MDD to
design and conduct studies that are capable of demonstrating such
benefits.I will return later to a
possible alternative approach to acute efficacy studies for demonstrating
antidepressant benefits of these drugs.

Origins of Present Concern About the Emergence of Pediatric Suicidality in Association
with Antidepressant Use; Initial Regulatory Response

Background to May, 2003 Paroxetine Report

After this brief look at the effectiveness issue, I want now to
return to the issue of the origins of the present concerns about pediatric
suicidality.My approach will be to give
a temporal perspective on how this issue has evolved over the past
approximately 7 months.The focus will
be on certain adverse events that were reported in the pediatric supplements
for the various antidepressants, in particular, adverse events considered to
represent suicidality.

First, it is important to comment on the approach used to elicit
treatment emergent suicidality in these trials.In part, investigators relied on very general prompts, e.g., asking the
general question of “how have things been” at each visit.While this approach is perhaps somewhat
superior to spontaneous reporting, it is likely a distinctly insensitive
approach to eliciting adverse events related to suicidality.Even in adults with MDD, it generally
requires a skilled clinician to elicit patient reporting of suicidal ideation
or behavior, and this tendency to conceal such ideation and behavior may be
even more prominent in adolescents.On
the other hand, all of these trials also utilized formal instruments for
assessing depressive symptoms, each of them including a suicidality item.However, it is not clear what elicitation
approaches were used in completing these instruments, and thus, it is not clear
whether or not there was specific elicitation with regard to suicidality.Furthermore, these instruments were not
always done at the times that patients were experiencing events of interest,
since such events occurred at random times.In order to adequately assess for such emergence of suicidal ideation
and/or behaviors, it is important to have methods that are sensitive to
detecting such effects.

In any case, verbatim (investigator) adverse events in any drug
development program, however they are elicited, are coded by subsuming them
under preferred terms in order to capture like events under the same term, even
if patients or investigators had used variable language to describe the
events.For these pediatric trials,
adverse events suggestive of suicidality were coded by the various sponsors for
their programs, using approaches unique to each program, and these data were
examined, along with numerous other adverse events, in the course of our
reviews of the pediatric supplements.FDA’s clinical reviews for these supplements, conducted over a several
year period prior to our becoming aware of a possible signal for the paroxetine
program, did not, overall, suggest a signal for drug treatment-induced
suicidality.

The Paxil review, however, did raise a question of data
management.The clinical reviewer for
the Paxil supplement noticed that events suggestive of possible suicidality
were subsumed under the preferred term “emotional lability,” rather than under
a preferred term more directly suggestive of suicidality.Other verbatim terms were also subsumed under
“emotional lability,” so one of our requests to GSK in our response letter to
their pediatric supplement for Paxil was to ask them to separate out for us the
verbatim terms suggestive of suicidality.This request was the basis for the additional work done by GSK on this
issue of suicidality that resulted in their submission of a report on
suicidality, first to the UK, and shortly thereafter, to FDA, on May 22,
2003.

This May 22, 2003 report suggested an increased risk (paroxetine
vs placebo) of various thoughts and behaviors coded as events considered
“possibly suicide related” and also for the subgroup of these events that met
the sponsor’s criteria for representing “suicide attempts.”The signal for increased risk was clearest
for 1 of the 3 trials involving pediatric patients with MDD.A summary of the sponsor’s findings for the
MDD trials in the Paxil program is included in Appendix 2.

Initial Regulatory Response to Signal of Increased Risk of Suicidality
for Paroxetine

The reaction to this report by the MHRA in the UK was very prompt, resulting in:

·A public
statement explicitly stating that paroxetine “should not be used in children
and adolescents under the age of 18 years to treat depressive illness,” and

·A labeling
change contraindicating paroxetine in pediatric MDD.

FDA’s response was soon to follow, with:

·A public
health advisory, stating that: “Although the FDA has not completed its
evaluation of the new safety data, FDA is recommending that Paxil not be used
in children and adolescents for the treatment of MDD.”

·Despite
the strong advisory, we did not take any labeling action, and in fact have not
taken any action on labeling as of the date of this memo.

Overview of FDA’s Ongoing Review
of Antidepressants and Pediatric Suicidality

GSK Approach to Accumulating Paroxetine Summary Data

First, I want to describe in some detail the approach GSK took in
evaluating their pediatric clinical trials data for suicidality, since we modeled
our request to sponsors of other antidepressants after the GSK approach, in
order to ensure that we would have similar data from different programs, for
comparative purposes.They focused
exclusively on placebo controlled trials (there were 6 such trials in the GSK
program), and that has been our focus as well.As noted earlier, in their original pediatric supplement, they had
subsumed events suggestive of suicidality under the preferred term “emotional
lability,” along with various other behavioral events.Subsequent to our request for a separate
approach to events suggestive of suicidality, they conducted the following
searches to find events of potential interest:

·Electronic
searches of their database with text strings of particular relevance for suicidality:

oSearch for all events for which the preferred
term was either “overdose” or “intentional overdose” (Note:They did not include any events for which the
preferred term was “accidental overdose”)

oSearch of verbatim (i.e., investigator) terms for
events that had originally been coded with the preferred term “emotional
lability,” in order to find verbatim terms including any of the following 15
text strings: “attempt; cut; gas; hang; hung; jump; mutilat; overdos; self
damag; self harm; self inflict; self injur; shoot; slash; suic”

oSearch of all verbatim terms containing the
text string “overdose” or “suic” (Note: They specifically excluded any
events for which the verbatim term selected was a result of the text string
occurring in another word that had no relevance to suicidality.)

·They
included in their analyses only patients having events that occurred either
during randomized treatment or in the +30 days posttherapy window, and only
events they judged to represent treatment-emergent events (However, treatment
emergent was not well-defined and no information was provided for any cases
excluded for not being considered treatment-emergent).All events meeting these criteria were
included under the broad category “possibly suicide related.”

·GSK then
created the subset of patients having events meeting their criteria for
“suicide attempt” using the following criteria:

oA text string suggestive of self-harm

oPreferred term “overdose” or “intentional
overdose”

oThey did exclude certain events judged
(blindly) by their own staff not to represent suicidality, however, no details
were provided on these patients or for the criteria used in excluding
cases

Request for Summary Data for Other Antidepressants

Following our initial review of the Paxil suicidality summary data,
we decided to ask for similar data for the other 8 antidepressants.We decided that it would be most efficient to
ask other sponsors to use a similar approach to that used by GSK in exploring
the Paxil data.Thus, we issued a letter
on July 22, 2003, requesting such summary data for the placebo controlled pediatric
studies for the 8 other antidepressant products for which such studies had been
conducted:

·Prozac
(fluoxetine)

·Zoloft
(sertraline)

·Luvox
(fluvoxamine)

·Celexa
(citalopram)

·Wellbutrin
(bupropion)

·Effexor
(venlafaxine)

·Serzone
(nefazodone)

·Remeron
(mirtazapine)

In this July 22nd letter, we asked the sponsors for these
products to identify “suicide-related events” for their pediatric studies, in a
“blinded” manner, using two search strategies.Since our request was modeled after the approach GSK had already used,
it included many of the same details provided above:

·Electronic
searches of their database with text strings of particular relevance for suicidality:

oSearch of preferred terms for the following 2
text strings:“suic” or “overdos”

§Note: We indicated that they may exclude instances
coded as accidental overdoses, but asked them to provide information on these
cases in a separate table.

§Note: We did indicate that terms identified using
these electronic searches because one of these text strings was included in a
word that had no relevance to suicidality could be excluded.

·In
addition, we asked them to blindly review narratives for any deaths and serious
adverse events (SAEs) in order to identify any additional possible instances of
“suicide-related events”

oNote: There were no deaths due to any cause in any of the 24 studies
included in these pediatric programs

·We also
asked the sponsors to blindly select from among the larger set of “suicide-related
events” a subset of events that could be consider “suicide attempts,” defined
to include all patients who exhibited self-injurious behavior.

·We asked
sponsors to provide a narrative for each patient identified as having one or
more potential events, and also a table including the same information for each
such patient.

The letter also asked for analyses for the cases identified using
these approaches similar to those described above for Paxil.

Re-Review of Suicidality Data from Pediatric Supplements for Other
Antidepressants

While we were waiting for the various sponsors of the
antidepressants other than Paxil to respond with their summary data, we went
back to the summary adverse event data in the pediatric supplements for these
other drugs to re-examine the question of suicidality.The major question of interest was whether or
not there were other antidepressants with possible signals of increased risk
for suicidality, as was observed for Paxil.There were several limitations to this re-examination.First, the methods for detecting and coding
events were not standard across these programs.Second, since we wanted to have similar numerator categories to those
used for the Paxil data, for purposes of comparison across drug programs, we
classified any events described in the adverse event listings, etc for these
drug programs into the two categories of interest: “possibly suicide-related”
and “suicide attempt.”One obvious flaw
in this approachwas
that the FDA reviewer was not blinded during this reclassification
process.Nevertheless, it was hoped that
this somewhat crude re-examination of these summary data might shed some light
on the possibility of signals emerging from other antidepressant programs.

While the methodology for this initial exploration was necessarily
crude, it did provide some further insight into the treatment-emergent
suicidality question across these 9 drug programs.There were several findings of particular
interest resulting from this crude look at the pediatric supplements data.First, there were signals of increased risk
of suicidality for patients assigned to drug for more than the paroxetine
program, and second, the findings were not consistent across the studies even
within individual programs.Finally, the
signals were coming predominantly from the MDD studies within these
programs.

During this period while we were re-examining the suicidality data
from the pediatric supplements and beginning to receive responses to our
requests for summary data from the sponsors for the other antidepressants,
Wyeth, the sponsor for Effexor (venlafaxine) and Effexor XR, decided to make
labeling changes for its products with regard to suicidality and
hostility.This action was based on its
re-analyses of the Effexor pediatric trials data.The labeling change was the addition of a
statement to the Usage in Children/Pediatric Use section of Precautions to note
increased reports of hostility and suicidality.This labeling change was accompanied by a Dear Health Care Professional
letter (August 22, 2003) noting the findings and also noting that these products are not
recommended for use in pediatric patients.It should be noted that sponsors have the authority to make changes of
this nature, i.e., that are perceived to strengthen labeling from the
standpoint of safety, without prior approval by FDA.

This action by Wyeth was followed in September, 2003 by a regulatory
response by the MHRA in the UK similar to their response to the report on
paroxetine suicidality data.They issued
a public statement advising that these products should not be used in pediatric
MDD, accompanied by a change in labeling to contraindicate these products in
pediatric MDD.FDA has not taken any
regulatory action based on these findings for venlafaxine, since we view these
as preliminary data that require the same level of more detailed review needed
for the other antidepressant drug products.

FDA Internal Regulatory Briefing

An important milestone in our consideration of the pediatric
suicidality data was an internal briefing for upper level CDER management held
on September 16, 2003.This briefing was held at a
time when we had available to us only a preliminary review of the summary data
for the Paxil program and a crude re-analysis of suicidality data from the
pediatric supplements, i.e., we had not yet received even the summary data from
the pediatric programs other than Paxil.There were several agreements reached at this meeting, including two
that were of particular importance for our further plans for addressing this
issue.It was acknowledged that a very
broad net had been cast in trying to capture events of potential interest with
regard to possible suicidality, and questions were raised about what many of
these events actually represented.Thus,
there was agreement that it would be useful to try to have all events of
potential interest blindly reclassified by outside experts in suicidality in
order to have greater confidence in what the signals represented.Second, there was acknowledgement that there
was inconsistency in the signals across individual studies for the various programs
for which signals of increased risk for suicidality emerged, based on the
re-analyses of pediatric supplement data.Thus, there was also agreement that it would be useful to attempt to
obtain patient level data sets for all of these trials in order to permit a
more refined analyses using adjustment for potentially important
covariates.These agreements strongly
influenced the subsequent course of our efforts to better understand these
data.

Updated FDA Public Health Advisory and Talk Paper

We issued an updated public health advisory and talk paper on October
27, 2003, based on
our assessment of the pediatric suicidality data at that point in time.We indicated that preliminary data suggested
an excess of reports of suicidality for several antidepressant drugs, however,
we noted that additional data and analysis would be needed.We also noted that we intended to bring this
issue to an advisory committee meeting.We advised caution in the use of any of these drugs in MDD, and reminded
prescribers of the standard language already in antidepressant labeling
alerting clinicians to the need for close supervision of high risk patients,
particularly during initial drug therapy.

Responses to FDA’s Request for Summary Data for Other
Antidepressants

Now I want to return to the summary data for the other
antidepressant drugs.The responses
including the requested data and analyses for these summary data began arriving
in late August, and had all arrived by late September, 2003.Unfortunately, as we began reviewing these
responses, it became clear that different sponsors had interpreted the July 22nd
request differently, resulting in our lack of confidence that the cases of
suicidality had been selected for review, classified, and presented to us using
similar approaches for all 8 sponsors.This impression was confirmed when we spoke to individual sponsors about
their approach to this request.In
retrospect, the algorithm we had provided for searching for potential events
and selecting patients with events for the summary data analyses was not
sufficiently detailed to result in a common understanding.This discovery presented a major hurdle to
overcome in our evaluation of these data, since we needed to have confidence in
the thoroughness and uniformity of the methods used for gathering and
classifying these cases.

I will provide at this point several examples of the kinds of
variations in methods we discovered across the different sponsors.This list of variations is just a sampling of
the types of variations, and should serve the purpose of making clear why we
needed to spend considerably more time ensuring that all relevant cases had
been accumulated, and that they had been appropriately classified.We felt this was critical in order for us to
complete our assessment of this potential problem.

We
had hoped to have a complete accounting of potential events identified by
the search algorithms and SAE narrative reviews,
however, in no case did a sponsor provide such an accounting.At one extreme we were provided
narratives only for patients judged by the sponsor to have events that
represented suicidality, with no explanation as to why other patients
identified by the algorithms might have been excluded.In other cases, more details were
provided on patients who had been excluded, but none of the reports was
completely satisfactory in this regard.

Although
most sponsors conducted the search and selection of cases according to our
instructions, in no case did they provide us with the specific criteria
used in excluding cases at various levels of the process.

For
example, although we invited sponsors to exclude cases that might be
considered “false positives” in the sense described above, i.e., where
the text string of interest occurred in a longer word that was irrelevant
to suicidality, we had expected that excluded cases would have been
described.Most sponsors did not
provide such a listing.

We
had asked for cases coded as accidental overdose, and for the most part
received this information, however, we had failed to inquire about cases
coded as accidental injury, and most sponsors did not fully address how
they handled these cases.In fact,
most sponsors simply excluded all cases coded as accidental injury,
without further review.As an
example, after we began inquiring about the process of excluding cases,
we received from one sponsor a line listing of excluded cases that
included a case of a child who was excluded as accidental injury with an
event characterized only as “patient stabbed himself in the neck with a
pencil while taking a test.”While
this may have in fact represented an accidental injury, we decided it
would be important to know enough details about cases coded as accidental
injury in order to be confident that such cases were appropriately
classified and excluded.

At
least one sponsor acknowledged that they had conducted some of the
searching and selection of cases with knowledge of treatment assignment,
in particular, for the review of narrative summaries of SAEs.

Another
sponsor acknowledged that they had excluded cases where the events that
occurred were not considered “treatment emergent.”These were events suggestive of
suicidality but for which there was evidence that the event may have also
been occurring before randomization.No other information had been provided about the excluded cases in
the sponsor’s summary submission.

Another
finding that raised concern about the approach to case exclusion and
selection resulted from our comparison of our results of suicidality risk
for one drug product based on our re-review of the pediatric supplements
with that sponsor’s analysis of suicidality based on their
reclassification of cases in response to our July 22nd
request.In this particular
instance, there was a striking difference in the results of the two analysis, i.e., a strong signal emerging from our
re-examination of the pediatric supplement for that drug compared to only
a weak signal emerging from the sponsor’s analysis submitted in response
to our July 22nd letter.

As
noted earlier, for many of the events included in the various analyses as
representative of suicidality, there were questions about whether or not
they were appropriately classified as such.Many of these were described as instances
of very minor self injury with no indication of suicidal intent.

There
were also substantial differences across different programs in the
selection of cases representing suicide attempts, with some sponsors
deciding to include essentially all captured events as suicide attempts,
even though there was clearly not enough information in the cases to
justify such a classification.

Decision to Seek Outside Review and Reclassification of Cases

During this period when we were re-examining the pediatric
supplement data and then beginning to explore the summary data provided to us
in response to our July 22nd letter, it was becoming increasingly
clear that we could not have confidence in the numerator events for the
analyses we were provided by the sponsors, because the methods were not well-articulated,
and the limited details available about the methods suggested that they varied
substantially for different sponsors.Thus, we essentially confirmed the view already reached tentatively at
our internal regulatory briefing that it would be desirable to have potential
events blindly reclassified by an independent group.We briefly considered doing this internally,
but quickly rejected this idea, since (1) we clearly did not have the expertise
in suicidality to conduct such a reclassification, and (2) most of those who
might logically be involved in such an effort had already seen many of the
cases.Thus, we began to look outside
the agency, and we initiated a series of discussions with outside experts.We found several experts interested in such
an effort, however, there remained the problem of who would coordinate the
overall effort, establish methods and criteria for reclassification, etc.Among the experts we discovered in our search
was a group at ColumbiaUniversity who not only had well-recognized expertise in
adolescent suicidality, but also had developed an approach to classifying
events possibly representative of suicidality that precisely fit our
needs.Thus we have been involved in
extensive discussions with this group in order to establish a contract for
having this reclassification of cases accomplished and also to work out the
details of a standard approach to both finding all relevant cases and setting
up categories for the reclassification effort that would meet our needs from a
regulatory standpoint.At the present
time, the contract is in place and we are in the process of preparing case
material to provide to this group.It is
important to note that, while the Columbia group will serve as the coordinating center
for this effort, experts in adolescent suicidality from several other academic
centers will also participate in the process in order to ensure broad
representation from the expert community.Once we have provided the case materials to this group, one of the
initial goals will be to try to reach agreement on an approach to classifying
events into appropriate categories.

Second Request for Identification of Events of Potential Interest
with Regard to Suicidality

As a result of our discussions with sponsors about their submissions
in response to our July 22nd request for summary data on suicidality
from their pediatric studies, and our discussions with the expert group at
Columbia University about the reclassification of these cases, we worked out a
more detailed standard method for sponsors to use in assembling their data
regarding any cases of potential interest detected in the searches of their
pediatric data base.This document was
provided to sponsors for all 9 antidepressant products on Nov 24,
2003.Following is a summary of key aspects of this
new standard:

We
asked sponsors to confirm that they had conducted an electronic search of
their preferred terms and verbatim terms using the text strings specified
in our July 22nd letter, or if not, to describe in detail what
they had done.

We
next asked sponsors to provide a complete accounting of the winnowing down
of the complete list of potential events/patients identified by these
electronic searches to arrive at the events that would need to be blindly
reclassified by outside experts.Sponsors were asked to provide the total number of patients
identified as having 1 or more such potential events suggestive of
suicidality, as a starting point.We then requested that they fully describe the exclusions from this
list, for the following reasons:

Prerandomization
events: Sponsors were to list all patients excluded because all of their
potential events occurred prerandomization.

Events
occurring more than 30 days beyond the last dose of randomized treatment:
Sponsors were to list all patients excluded because all of their
potential events occurred more than 30 days beyond the last dose of
randomized treatment.

False
positive events:Sponsors were to
list all patients excluded because all of their potential events could be
characterized as “false positives” in the sense that a preferred or
verbatim term was selected because one of the text strings occurred
within that term and the term has no relevance to suicidality, e.g.,
“gas” in “gastrointestinal.”

We
asked for summary narratives for all remaining patients with potential
events, including patients classified as having accidental injury or
accidental overdose (i.e., using preferred terms).

In
addition, we asked sponsors to provide narratives for all patients having
one or more serious adverse events (SAE, based on regulatory definition)
that occurred either in the randomized doubleblind phase of the controlled
trials or within the +30 days beyond the last randomized dose period
described earlier.

Blinded Reclassification of Potential Suicidality Events

We have now received responses to this Nov 24th request
from most of the sponsors, and, as noted, we are in the process of preparing
this information to forward to our outside contractors.We expect to be working closely with them
over the next month in order to reach agreement on (1) the approach they will
use in cleaning and blinding the narratives for information that might bias
their assessment (to be done by an independent group who will not be involved
in the reclassification of events), (2) the categories into which events will
be classified and the criteria for such placements, (3) the process by which
disagreements will be resolved, or if not resolved, the process for reaching
the best judgement for classifying any particular case.We expect that it will take at least anotherseveral
months to complete this reclassification effort.A member from the Columbia group will be making a presentation at the Feb
2nd meeting to describe their role in this project in greater
detail.

There is one caveat to this effort.It is ultimately limited by 2 significant problems.First, as noted earlier, the approach to
eliciting suicidal ideation and behavior was of unknown sensitivity.Second, the approach to identifying potential
events may have missed certain events if they were not classified as serious,
since detection for the other events depended on matching on certain text
strings, and the list of text strings was necessarily limited.

Interim Overview of Results from Sponsors’ Analyses of their
Original Summary Data (i.e., for drugs other than Paxil)

Given that we are not confident in what the numerator data represent
in the summary analyses provided by the sponsors for these pediatric studies,
we will not be presenting detailed results from these analyses at this
time.However, I have included one
summary data table (Appendix 2) in
order to make two important observations.Appendix 2 summarizes risk
data by individual study for the 15 pediatric major depressive disorder (MDD)
studies for which we have data.While we
have been provided data both for “on-therapy” and for “on-therapy + 30 days”
events, I have focused on the “on-therapy” data, since these are the least
problematic from the standpoint of interpretation.While we do sometimes utilize an “on-therapy
+ 30 days” timeframe for capturing events of interest, this analysis is
problematic in this case for two reasons. First, it may be confounded by
discontinuation symptoms occurring following withdrawal of medication, and
second, different sponsors used different rules in deciding what events to
include and exclude from the +30 days period in their analyses.For simplicity, I have provided the data for
all ages combined, rather than breaking it out by age group.The table provides risk (percentage of
patients having at least 1 event) and risk ratio (when this can be
calculated).Risk is provided both for
the category “possibly suicide-related” and the subgroup of events classified
as “suicide attempts.”

I think there are two important observations from this table:

(1)A signal of increased risk on drug is apparent
for at least 4 of the 7 programs, i.e., paroxetine, sertraline, venlafaxine,
and citalopram, with perhaps a weak signal for nefazodone.

(2)There is inconsistency across the individual
studies within the programs for which there is an apparent signal, with the
exception of venlafaxine, where both studies reveal a signal.For paroxetine, a signal emerges from 1 study
(329), but without even a weak signal for the other 2 studies in the
program.This is also the case for
sertraline and citalopram, where a signal emerges from 1 of 2 studies in each
case, with no signal emerging in the other study.While fluoxetine is generally without a
signal, in the “suicide attempts” analysis for study X065 there is actually a
signal for drug.There are several
instances where the risk ratio favors drug over placebo.

Overall, I think Appendix 2
reveals that, while there are signals of increased risk of events suggestive of
suicidality for several of these drugs, the signals for the most part are
coming from a single trial within each of these programs.An important additional point, however, is that
we are not yet confident in what the identified events represent.

Planned Analyses of Patient Level Data for Pediatric
Suicidality

As noted earlier, the observation of inconsistency of the signal
across studies within individual programs based on a crude re-analysis of
suicidality from the pediatric supplements resulted in a recommendation from
our internal regulatory briefing to request patient level data to permit us to
conduct a more refined analysis including adjustment for potentially important
covariates.Since the summary data
provided by the sponors in response to our July 22, 2003 request have confirmed that finding of
inconsistency, we are planning on proceeding with this more detailed analysis
of the suicidality data from these programs.A standard letter requesting patient level data sets was issued to all
sponsors on October 3, 2003.The
variable list was expanded several times in subsequent weeks, and the final
variable list is included as Appendix 3.We have now received all of these data sets
from sponsors, and we are in the process of developing an analysis plan to
explore for excess risk of suicidality using a statistical model that provides
for adjustment of covariates.The
numerator events for this analysis will be identified based on the
reclassification of patient events by our outside experts.A member of our safety group will make a
presentation on the current status of our plans for this analysis at the Feb 2nd
meeting.

Update on Most Recent
Regulatory Action on Antidepressant Treatment of Pediatric MDD by MHRA

The MHRA (UK) made a public announcement on Dec 10,
2003 indicating that,
in addition to its earlier contraindications of paroxetine and venlafaxine in
pediatric MDD, it was now contraindicating sertraline, citalopram, and
escitalopram as well for this condition.This announcementnoted that the risk benefit profile is unassessable for
fluvoxamine, and that, in its view, the risk benefit profile is favorable in
pediatric MDD only for fluoxetine.

[Note: Nefazodone and bupropion are not approved drug
products in the UK.Mirtazapine is an approved
product in the UK, however, MHRA has offered no comment on the
pediatric data for this drug.]

Summary of Issues That
Complicate the Anaylsis of the Pediatric Suicidality Data; Questions for the
Committee

In this section, I will first recap the major issues that have
complicated our attempts to understand the pediatric suicidality data, and then
list the specific issues for which we would like committee feedback to assist
us as we move forward in trying to address this concern.We are not asking for votes on any particular
questions, but rather, discussion by the committees and any feedback you might
have to offer on our current plans for further exploring these data.

Ascertainment for Suicidality

One of the concerns about these studies is the fact that they were
not conducted in a manner to fully and adequately assess patients for emergent
suicidality.This is apparent in
reviewing the descriptive information for the events identified as possibly
suggestive of suicidality.These
descriptions are frequently sparse and lacking the kind of detail that would
ordinarily be useful in assessing whether or not the events might legitimately
be considered to represent suicidality.There is, of course, no fix for this problem with regard to these
studies.However, one of our outside
experts will address the issue of how one might develop guidance for more
adequate assessment for emergent suicidality in future studies.We would welcome any advice from the
committees on the development of such guidance.

One might reasonably ask why this would be a concern for these
studies, since, despite the generally inadequate ascertainment, signals for
drug associated suicidality did emerge.In fact, however, one can easily construct possible explanations for
biases being introduced by inadequate ascertainment that work either for drug
or against drug.Rather than having to
speculate about possible bias, it would have been preferable to have included
adequate ascertainment in the first place.

Possible Failure to Fully Capture All Events of Potential Interest
with Regard to Suicidality

Quite apart from a concern about ascertainment is the issue of the
method used to search the database for events of possible interest.GSK had developed an algorithm for searching
for potential events representing suicidality in their database, and we
proposed a variation of this to other sponsors.However, this is admittedly a compromise. It is still conceivable that
certain cases of interest might have been missed by the search methods
employed.The only failsafe approach to
identifying all possible events of interest would be to have experts blindly
evaluate every case report form for the more than 4000 patients who
participated in these trials.Since that
is not feasible, we welcome advice from the committee on possible modifications
to the search strategies used for identifiying cases that might have been missed.Additional searches at this point would
further delay the analyses of these data, and so this needs to be taken into
consideration.However, if the
committees feel there are serious deficiencies in the search methods employed,
it would be helpful to hear about alternative approaches that might be
suggested.

Approaches to Classifying Events into Meaningful Categories for the
Purpose of Further Analysis

As noted, an important next step is to decide on categories into
which events of interest might be classified, along with operational definitions
for such classifications.The approach
used by sponsors thus far has been to classify cases first into a crude
category of “possibly suicide-related,” and then a further subgrouping of that
broader group into a “suicide attempt” class.Since we are just now beginning to address this question with our
outside experts, we would welcome any advice the committees might have on how
to classify these events for the purpose of further analysis.

Patient Level Data Analysis

There will be a brief presentation by a member of our safety group
on our plans for the patient level data analysis.Since we are in the preliminary stages of
this analysis, this would again be an opportune time to get feedback on how to
approach this analysis.In addition, you
have seen our list of potential covariates for inclusion in this analysis, and
we would welcome any thoughts you might have on this list.If we have left out important covariates,
please let us know, since this would be the time to try to gather any additional
information that you feel might be helpful in trying to understand these
data.

Future Approaches to Trying to Address the Question of What Benefits
These Drugs Might Have in Pediatric MDD

As noted earlier, the attempts to demonstrate efficacy in short-term
trials for these drugs have not been successful, for the most part.We would welcome your thoughts on how to
interpret and understand these largely negative results, and also any thoughts
you might have on alternative approaches to demonstrating benefits in this
population.An approach often used in
expanding information on effectiveness in adult MDD populations is the
randomized withdrawal design, in which patients who have responded during open
treatment with an antidepressant drug are randomized to either continuation of
drug or switch to placebo.The endpoint
in these trials is typically time to relapse, and the success rate for these
trials is far higher than the roughly 50% success rate in acute trials in adult
MDD.We would welcome your thoughts on
whether or not this design might be useful in evaluating possible benefits of
these drugs in pediatric MDD.

Feedback on Other Relevant Topics

You should not feel limited to providing feedback on the above
topics.The purpose of this meeting is
to give you interim feedback on where we are at present with our attempts to
understand these data, and to gain your insights into how we might
proceed.Thus, we would welcome your
feedback on other issues as well that you feel are relevant to our continuing
evaluation of these data.

[Note: This was the
final variable list submitted to sponsors (10-28-03) as an update to the original request for
patient level data sets send 10-3-03]

We would appreciate your adding these variables to the
previously requested dataset.

HXPSHOSP: This is a Y/N variable indicating that the subject
had a history of psychiatric hospitalization prior to entering the RCT.

SCALESUI: The score of the suicide item for the primary
scale used to rate baseline severity of depression. As part of your response to
this data request, please include the range and meaning of the scores for the
suicide item.

Clarifications of 10/27/03
updated request:

·Please note that the description of the variable
HXSUIATT referred to history of suicide attempts. The description should
be corrected to read “attempt” (see table below). In other words, to qualify
for a “yes” on that variable, a subject need only have had one suicide attempt
(not multiple).

·“.” Will be added as a response option for
missing data for the psychiatric history variables

·In the variable “HXNONCOM”, “erratic” compliance
is defined as not taking the study drug as prescribed.

The changes described above are highlighted in the following table.

Variable name

Length

Type

Description

Coding notes

TRIAL

NS

Character

Trial ID

No missing values are
allowed in this variable.

CTPID

NS

Character

Patient ID within each trial.

No missing values are
allowed in this variable

UNIQUEID

NS

Character

A unique ID for every patient

It should incorporate both the trial ID and the patient ID
within each trial.

No missing values are
allowed in this variable.

DIAG

NS

Character

Condition for which
patient was being treated (e.g.,dementia-related psychosis or
schizophrenia).

Should be one of the
diagnoses listed for the corresponding trial in the “Controlled Trial File”.

No missing values are
allowed in this variable.

DIAGCAT

3

Numeric

Diagnosis category

1= major depressive
disorder

2= obsessive
compulsive disorder

3= social anxiety
disorder

4= other anxiety
disorder

AGE

3

Numeric

Age of patient in years

. = Missing.

AGECAT

3

Numeric

Categories of age

1= AGE < 12

2= AGE >= 12

. = Missing

GENDER

3

Numeric

Patient gender

1= Female

2= Male

. = Missing

RACE

3

Numeric

Race

1= White Caucasian

2= African-American
3= Hispanic

4= Asian

5= Other

. = Missing

BMI

3

Numeric

Body mass index

Calculated as weight in kg/(height in meters)2

. = Missing

SET

3

Numeric

Setting at randomization

1= Inpatient

2= Outpatient

. = Missing

LOC

3

Numeric

Location of trial center

1= North America

2= Non-north America

. = Missing

HXSUIATT

3

Numeric

The subject had a history of suicide attempt prior to
entering the RCT

0=No

1=Yes

. =
Missing

HXSUIID

3

Numeric

The subject had a history of suicidal ideation prior to
entering the RCT

0=No

1=Yes

. =
Missing

HXPSHOSP

3

Numeric

The
subject had a history of psychiatric hospitalization prior to entering the
RCT

0=No

1=Yes

. =
Missing

HXSUBAB

3

Numeric

The subject had a history of substance abuse prior to
entering the RCT

0=No

1=Yes

. =
Missing

HXHOST

3

Numeric

The subject had a history of hostility or aggressive
behavior prior to entering the RCT

0=No

1=Yes

. =
Missing

HXIRRAG

3

Numeric

The subject had a history of irritability or agitation
prior to entering the RCT

0=No

1=Yes

. =
Missing

RANTX

NS

Character

Name of
post-randomizationtreatment
assignment

”Your drug name”,“Placebo”, or the name of the active
control drug

No missing values are
allowed in this variable.

RANTXCAT

3

Numeric

Category of the
drug

1=SSRI

2=non-SSRI

3=placebo

DOSE

3

Numeric

Dose of the post-randomization
investigational treatment; If a flexible dose scheme was used, then
report the modal dose. If there were multiple modal doses, select the maximal
modal dose

0=Placebo

. = Missing

DFRAN

10

Date

Date of first dose of randomized treatment

Use date format: MM /DD/YYYY, e.g. 3/4/2000

. = Missing

DLRAN

10

Date

Date of last dose of randomized treatment

Use date format: MM /DD/YYYY e.g. 6/14/2000

. = Missing

EXPOSURE

3

Numeric

Number of days of exposure to randomized treatment

Should represent the difference between “DFRAN” and
“DLRAN”.

[DLRAN-DFRAN]+1

. = Missing

HXNONCOM

3

Numeric

There is some evidence in the
subject’s medical record or case report form that the subject had a history
of erratic compliance with the study medication during the RCT

The score of the suicide item for the primary scale
used to rate baseline severity of depression

. =
Missing

DURATION

[Add DURACAT variable if duration of illness was recorded
as a categorical variable]

3

Numeric

Duration of illness prior to randomization in months

. = Missing

SUIEVENT

3

Numeric

A suicide-related event as defined in July 2003 submission
occurred during the RCT

0= No

1=Yes

SUIATT

3

Numeric

A suicide attempt as defined in July 2003 submission
occurred during the RCT [Suicide attempt is a subset of suicide-related
event]

0=No

1=Yes

EVENTDC

3

Numeric

The first suicide-related event occurred following
discontinuation

0=No

1=Yes

DAYEVENT

3

Numeric

The number of days to the first suicide-related
event counting from the day of the first dose. Counting from the first day of
drug should occur even if the event occurred after the patient discontinued
the drug.

. = Missing or patient did not have an event

TEAEAG

3

Numeric

A treatment-emergent adverse event coded to the preferred
term agitation occurred during the RCT

0=No

1=Yes

TEAEHOST

3

Numeric

A treatment-emergent adverse event coded to the preferred
term hostility occurred during the RCT

Wagner KD, Ambrosini P, Rynn M, et al: Efficacy of sertraline in the
treatment of children and adolescents with major depressive disorder.JAMA 2003; 290(8):1033-1041.

cc:

HFD-120/TLaughren/RKatz/JRacoosin/PDavid

HFD-040/RTemple

HFD-020/JJenkins

DOC:PDAC_Memo_Feb2004_TL02.doc

[1]I will distinguish between what I will refer
to as summary dataandpatient level data.Summary data will refer to data tables provided by sponsors that include
only numbers of events as numerators and either total patients exposed or total
accumulated person-time as denominators.Patient level data will refer to data sets provided by sponsors in
response to detailed requests made by FDA for electronic data sets structured
to include one row per patient participating in each study, with multiple
variables for each patient.Patient
level data sets permit adjustments for potentially important covariates, while
summary data do not.